T cells in the skin: lymphoma and inflammatory skin disease.

T cells are established contributors to the pathogenesis of atopic dermatitis (AD) and psoriasis, yet whether they are the key drivers or simply unwitting participants remains incompletely understood. Conversely, malignant T cells are the undisputed culprits of cutaneous T cell lymphoma (CTCL), a group of diseases that share key clinical, histopathological and molecular features with inflammatory skin disease (ISD). Here, we compare the pathogenesis of ISD and CTCL and discuss the resulting insights. Recurrent, skin-limited disease implicates skin-resident T cells (TRM) in both ISD and CTCL. In CTCL, malignant T cells recruit benign T cells into inflammatory skin lesions, a disease-amplifying function also proposed for pathogenic T cells in ISD. Mechanistically, cytokines produced by malignant T cells in CTCL and by pathogenic T cells in ISD, respectively, are likely both necessary and sufficient to drive skin inflammation and pruritus, which in turn promotes skin barrier dysfunction and dysbiosis. Therapies for ISD target T cell effector functions but do not address the chronicity of disease while treatments for CTCL target malignant T cells but not primarily the symptoms of the disease. By integrating our understanding of ISD and CTCL, important insights into pathogenesis and therapy can be made which may improve the lives of sufferers of both disease groups

Anti-aquaporin 4 IgG Is Not Associated With Any Clinical Disease Characteristics in Neuromyelitis Optica Spectrum Disorder

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a clinically defined, inflammatory central nervous system (CNS) disease of unknown cause, associated with humoral autoimmune findings such as anti-aquaporin 4 (AQP4)-IgG. Recent clinical trials showed a benefit of anti-B cell and anti-complement-antibodies in NMOSD, suggesting relevance of anti-AQP4-IgG in disease pathogenesis. Objective: AQP4-IgG in NMOSD is clearly defined, yet up to 40% of the patients are negative for AQP4-IgG. This may indicate that AQP4-IgG is not disease-driving in NMOSD or defines a distinct patient endotype. Methods: We established a biobank of 63 clinically well-characterized NMOSD patients with an extensive annotation of 351 symptoms, patient characteristics, laboratory results and clinical scores. We used phylogenetic clustering, heatmaps, principal component and longitudinal causal interference analyses to test for the relevance of anti-AQP4-IgG. Results: Anti-AQP4-IgG was undetectable in 29 (46%) of the 63 NMOSD patients. Within anti-AQP4-IgG-positive patients, anti-AQP4-IgG titers did not correlate with clinical disease activity. Comparing anti-AQP4-IgG-positive vs. -negative patients did not delineate any clinically defined subgroup. However, anti-AQP4-IgG positive patients had a significantly (p = 0.022) higher rate of additional autoimmune diagnoses. Conclusion: Our results challenge the assumption that anti-AQP4-IgG alone plays a disease-driving role in NMOSD. Anti-AQP4-IgG might represent an epiphenomenon associated with NMOSD, may represent one of several immune mechanisms that collectively contribute to the pathogenesis of this disease or indeed, anti-AQP4-IgG might be the relevant factor in only a subgroup of patients

Effects of ram pressure on the gas distribution and star formation in the Large Magellanic Cloud

We use high resolution N-body/SPH simulations to study the hydrodynamical interaction between the Large Magellanic Cloud (LMC) and the hot halo of the Milky Way. We investigate whether ram-pressure acting on the satellite's ISM can explain the peculiarities observed in the HI distribution and the location of the recent star formation activity. Due to the present nearly edge-on orientation of the disk with respect to the orbital motion, compression at the leading edge can explain the high density region observed in HI at the south-east border. In the case of a face-on disk (according to Mastropietro et al. 2008 the LMC was moving almost face-on before the last perigalactic passage), ram-pressure directed perpendicularly to the disk produces a clumpy structure characterized by voids and high density filaments that resemble those observed by the Parkes HI survey. As a consequence of the very recent edge-on motion, the H-alpha emission is mainly concentrated on the eastern side where 30 Doradus and most of the supergiant shells are located, although some H-alpha complexes form a patchy distribution on the entire disk. In this scenario only the youngest stellar complexes show a progression in age along the leading border of the disk.Comment: 18 pages, 18 figures, submitted to MNRA

Cutaneous Immune Cell-Microbiota Interactions Are Controlled by Epidermal JunB/AP-1

Atopic dermatitis (AD) is a multi-factorial skin disease with a complex inflammatory signature including type 2 and type 17 activation. Although colonization by S. aureus is common in AD, the mechanisms rendering an organism prone to dysbiosis, and the role of IL-17A in the control of S. aureus-induced skin inflammation, are not well understood. Here, we show several pathological aspects of AD, including type 2/type 17 immune responses, elevated IgE, barrier dysfunction, pruritus, and importantly, spontaneous S. aureus colonization in JunBΔep mice, with a large transcriptomic overlap with AD. Additionally, using Rag1-/- mice, we demonstrate that adaptive immune cells are necessary for protection against S. aureus colonization. Prophylactic antibiotics, but not antibiotics after established dysbiosis, reduce IL-17A expression and skin inflammation, examined using Il17a-eGFP reporter mice. Mechanistically, keratinocytes lacking JunB exhibit higher MyD88 levels in vitro and in vivo, previously shown to regulate S. aureus colonization. In conclusion, our data identify JunB as an upstream regulator of microbiota-immune cell interactions and characterize the IL-17A response upon spontaneous dysbiosis.We thank the Wagner lab for helpful suggestions and discussion throughout the evolution of this project, specifically Alvaro Ucero, Nuria Gago, and Liliana Mellor. We thank Vanessa Bermeo and Guillermo Medrano for help with animal husbandry and genotyping. O.U. was funded by the ECTS/Amgen Bone Biology Fellowship (2013-2016) and by the Spanish Ministry of Economy and Competitiveness (SAF2012-39670). B.R. and W.W. were funded by a Jesus-Serra visiting scientist grant. E.F.W. was funded by a European Research Council advanced grant (ERC FCK/2008/37).S

Do High-Velocity Clouds trace the Dark Matter subhalo population?

Within the cosmological concordance model, Cold Dark Matter (CDM) subhalos form the building blocks which merge hierarchically to more massive galaxies. Since intergalactic gas is accreted by massive galaxies, observable e.g. as high- velocity clouds (HVCs) around the Milky Way, with extremely low metallicities, these can be suggested to represent the baryonic content of primordial Dark Matter (DM) subhalos. Another possibility of their origin is that they stem from disrupted satellite galaxies, but in this case, these gas clouds move unaccompanied by a bound DM structure. Since HVCs are observed with long gas tails and with irregular substructures, numerical models are performed aiming at exploring their structure and compare them with observations. If HVCs are engulfed by DM subhalos, their gas must leave the DM gravitational potential and reflect this in their dynamics. On the other hand, the evolution and survival of pure gas models must be tested to distinguish between DM-dominated and DM-free clouds and to allow conclusions on their origin. The models demonstrate that purely baryonic HVCs with low masses are disrupted by ram-pressure stripping and Kelvin-Helmholtz instabilities, while more massive ones survive, losing their initially spherical shape and develop significant substructures including cometary elongations in the column density distribution ("head-tail structure"). On the contrary, HVCs with DM subhalos survive with more than 90% of their gas mass still bound and spherically shaped, approaching the Galactic disk like bullets. In addition, we find that velocity gradients along the cometary head-tail structures does not necessarily offer a possibility to distinguish between DM-dominated and purely gaseous HVCs. Comparison of models with observations let us conclude that HVCs are not embedded in a DM substructure and do not trace the cosmological subhalo population.Comment: Accepted for publication in A&

Macrophage development and activation involve coordinated intron retention in key inflammatory regulators

Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes/proteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response

Partial loss of actin nucleator actin-related protein 2/3 activity triggers blebbing in primary T lymphocytes

T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin‐related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F‐actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3‐knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon‐like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three‐dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3‐dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities

Whiteness and loss in outer East London: tracing the collective memories of diaspora space

This paper explores collective memory in Newham, East London. It addresses how remembering East London as the home of whiteness and traditional forms of community entails powerful forms of forgetting. Newham's formation through migration – its ‘great time’ – has ensured that myths of indigeneity and whiteness have never stood still. Through engaging with young people's and youth workers' memory practices, the paper explores how phantasms of whiteness and class loss are traced over, and how this tracing reveals ambivalence and porosity, at the same time as it highlights the continued allure of race. It explores how whiteness and class loss are appropriated across ethnic boundaries and how they are mobilized to produce new forms of racial hierarchy in a ‘super-diverse’ place